Abstract |
Tumor-specific translocations are common in tumors of mesenchymal origin. Whether the translocation determines the phenotype, or vice versa, is debatable. Ewing's family tumors (EFT) are consistently associated with an EWS-FLI1 translocation and a primitive neural phenotype. Histogenesis and classification are therefore uncertain. To test whether EWS-FLI1 fusion gene expression is responsible for the primitive neuroectodermal phenotype of EFT, we established a tetracycline-inducible EWS-FLI1 expression system in a rhabdomyosarcoma cell line RD. Cell morphology changed after EWS-FLI1 expression, resembling cultured EFT cells. Xenografts showed typical EFT features, distinct from tumors formed by parental RD. Neuron-specific microtubule gene MAPT, parasympathetic marker cholecystokinin, and epithelial marker keratin 18 were up-regulated. Conversely, myogenesis was diminished. Comparison of the up-regulated genes in RD-EF with the Ewing's signature genes identified important EWS-FLI1 downstream genes, many involved in neural crest differentiation. These results were validated by real-time reverse transcription-PCR analysis and RNA interference technology using small interfering RNA against EWS-FLI1 breakpoint. The present study shows that the neural phenotype of Ewing's tumors is attributable to the EWS-FLI1 expression and the resultant phenotype resembles developing neural crest. Such tumors have a limited neural phenotype regardless of tissue of origin. These findings challenge traditional views of histogenesis and tumor origin.
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Authors | Siwen Hu-Lieskovan, Jingsong Zhang, Lingtao Wu, Hiroyuki Shimada, Deborah E Schofield, Timothy J Triche |
Journal | Cancer research
(Cancer Res)
Vol. 65
Issue 11
Pg. 4633-44
(Jun 01 2005)
ISSN: 0008-5472 [Print] United States |
PMID | 15930281
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- EWS-FLI fusion protein
- Oncogene Proteins, Fusion
- Proto-Oncogene Protein c-fli-1
- RNA-Binding Protein EWS
- Transcription Factors
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Topics |
- Animals
- Cell Differentiation
(genetics)
- Cell Line, Tumor
- Gene Expression Regulation, Developmental
(genetics)
- Gene Expression Regulation, Neoplastic
(genetics)
- Humans
- Mice
- Mice, SCID
- Neoplasm Transplantation
- Neural Crest
(embryology, metabolism, physiology)
- Oncogene Proteins, Fusion
(genetics)
- Proto-Oncogene Protein c-fli-1
- RNA-Binding Protein EWS
- Rhabdomyosarcoma, Embryonal
(genetics, metabolism, pathology)
- Sarcoma, Ewing
(genetics, metabolism, pathology)
- Transcription Factors
(genetics)
- Transfection
- Transplantation, Heterologous
- Up-Regulation
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